Neuron dysfunction and death are hallmarks of neurodegenerative diseases that deviate from normal aging in the CNS. Alzheimer's (AD) and Parkinson's disease (PD) are distinctly different neurodegenerative disorders, but PD patients may develop a progressive dementia, and extra- pyramidal signs may emerge in classic AD. Further, AD neurofibrillary tangles and senile plaques may accumulate in the brains of demented PD patients. When the brains of AD patients contain numerous PD lesions, i.e. Lewy bodies (LBs), this represents the LB variant of AD (LBVAD), or AD with diffuse LB disease (DLBD), but when cortical LBs are the only brain lesions in a demented elderly patient, this represents pure DLBD. Overlap of AD and LB disorders is common, but poorly understood, and the mechanisms of disease progression have not been established in AD or LB disorders. This Program Project will address this issue. To do this, Program Project investigators build upon substantial accomplishments of the previous funding cycle and on supportive Administrative , Clinical and Neuropathology Cores. The clinical core recruits and follows well characterized controls and patients with AD and/or LB disorders. The neuropathology core performs apolipoprotein E (APOE) genotyping and postmortems on subjects followed in the clinical core. Four related Projects focus on mechanisms of neuron dysfunction and death in Ad and LB disorders. Briefly, the first Project studies the composition of LBs and the consequences of LB formation in neurons of the postmortem brain. These studies are extended to transgenic mice that express the high molecular weight neurofilament (NF) subunit (NFH) fused to the LacZ gene since these NFH/LacZ transgenic mice accumulate NF-rich LB-like inclusions in association with neuron loss as a function of age. The next Project studies degeneration of dopaminergic pathways in AD and LB disorders, and it extends these studies to the NFH/LacZ mice since they accumulate LB-like inclusions in midbrain dopaminergic neurons. Alterations in signal transduction mediated by phospholipid derived second messengers associated with neuron degeneration in AD and LB disorders are the theme of the next Project which also extends its inquires to the NFH/LacZ mice as a model of LB diseases. Finally, the last Project investigates disruption of the neuronal cytoskeleton in AD and LB diseases by elucidating the role of brain phosphatases in the pathogenesis of neurofibrillary lesions. Taken together, this Program Project renewal is an integrated and focused multi-disciplinary effort to elucidate mechanisms that lead to the degeneration of selectively vulnerable neurons in AD and LB diseases. The proposed studies will contribute to the development of strategies to improve the diagnosis and therapy of Ad, PD and related LB disorders.